The document discusses inpatient management of hyperglycemia. It provides an overview of studies showing associations between hyperglycemia and poor outcomes in hospitalized patients. It then reviews interventional studies demonstrating that intensive insulin therapy targeting tighter glucose control can improve outcomes. The document discusses strategies for glucose management in the hospital, barriers to control, and different insulin regimens that can be used.

1. Inpatient Management of Hyperglycemia Russell Vinik, M.D. Hospitalist, University of Utah

2. Overview Observations related to hyperglycemia and outcomes in hospitalized patients Potential mechanisms for poor outcomes in hyperglycemic patients Review interventional studies related to glucose management Strategies for improving inpatient control

3. Umpierrez GE et al. J Clin Endocrinol Metab . 2002;87:978-982. Hyperglycemia Is an Independent Marker of Inpatient Mortality in Patients With Undiagnosed Diabetes In-hospital Mortality Rate (%) Newly Discovered Hyperglycemia Patients With History of Diabetes Patients With Normoglycemia P < 0.01 P < 0.01

4. Postoperative Glycemic Control Correlates With Cardiac-Related Mortality * ( P <.001). Furnary AP et al. J Thorac Cardiovasc Surg . 2003;125:1007-1021. Mortality (%) 0.9 1.3 2.3 4.1 6.0 14.5 Average Postoperative Glucose (mg/dL) * * * *

5. Poor Outcomes Correlate With Hyperglycemia After Acute Ischemic Stroke Williams LS et al. Neurology . 2002;59:67-71. Blood Glucose at Admission .015 .07 .15 .018 .009 7.2 ± 0.4 73% 7% 10% 18% 6 ± 0.3 79% 5% 5% 11% Length of stay Discharged to home In-hospital mortality 30-Day mortality 1-Year mortality P value BG  130 mg/dL (n=258) BG <130 mg/dL (n=385) Outcome

6. Rates of Nosocomial Infection in 100 Uninfected Diabetics Undergoing Elective Surgery Glucose on Post-Op Day #1 Pomposelli et al. JPEN 1998; 22:2, 77-81

7. Hyperglycemia and Poor Outcomes Following Myocardial Infarction Arch Intern Med. 2009;169(5):438-446 In Hospital Mortality (%) Average Post-admission Glucose

8. Basic Science Hyperglycemia is associated with increased neuron damage following brain ischemia Hyperglycemia leads to increased platelet aggregation and thrombosis Insulin decreases arterial levels of free fatty acids Hyperglycemia leads to increased cytokine levels and inflammation Neutrophil Adherence, chemotaxis, phagocytosis and extravasation are all inhibited by increased glucose concentrations Diabetes Care. 2004;27:553-591, Diabetes 1989;38:1031-5, Diabetes Care 2001;24:1634-9

9. Intervention Studies

10. Insulin and Sternal Wound Infections Furnary et al studied 2467 patients undergoing open heart operations The first 968 patients were treated with a sliding scale to keep glucose near 200 The next 1499 patients received an insulin infusion to keep glucose 150-200 Ann Thorac Surg 1999;67:352-62

11. Insulin and Sternal Wound Infections Furnary AP et al. Ann Thorac Surg . 1999;67:352-362. 4 3 2 1 0 DSWI (%) 87 88 89 90 91 92 93 94 95 96 97 Year CII Patients with diabetes Nondiabetic patients

12. Insulin and Mortality in CABG patients CII Year Furnary AP Endocr Pract . 2004;10(suppl 2):21-33. Mortality

13. Intensive Insulin in the Critically Ill- (Leuven I) Van Den Berghe et al enrolled 1548 ventilated patients mostly post cardiac surgery 13% of these patients had diabetes Patients were randomized to: intensive treatment - infusion to maintain glucose between 80-110mg/dl conventional treatment- targeting a glucose of 180-200mg/dl Mean glucose in the intensive treatment group was 103 and conventional group was 153 Hypoglycemic events (glucose<40) occurred in 5.1% of patients in the intensive treatment group vs. 0.76% of patients in the conventional group Van den Berghe G et al. NEJM 2001;345: 1359-67

14. Intensive Insulin in the Critically Ill Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367. 100 96 92 88 84 80 0 0 20 40 60 80 100 120 140 160 Intensive treatment Conventional treatment Intensive treatment Conventional treatment Survival in ICU (%) 100 96 92 88 84 80 0 0 50 100 150 200 250 In-Hospital Survival (%) Days After Admission Days After Admission 42.5% reduction in mortality with intensive treatment; P <.04 34% reduction in mortality with intensive treatment; P <.01

15. Benefits of IV Insulin Treatment in Critically Ill Hospitalized Patients Van den Berghe G et al. N Engl J Med. 2001;345:1359-1367. Reduction (%) 34% 46% 41% 50% 44%

16. Krinsley JS. Mayo Clin Proc. 2004;79:992–1000 . The Stamford Project Mixed medical/surgical/cardiac ICU “ Before-and-after” design Developed an insulin protocol and followed 800 consecutive patients Compared the outcomes in these patients to a control group of 800 consecutive patients immediately prior to protocol institution Targeted a blood glucose of less than 140

17. Stamford Project: Improvement in Mortality * *P <.01 compared with control group. † P <.05 compared with control group. † * † Krinsley JS. Mayo Clin Proc . 2004;79:992-1000. Decrease in Mortality With Treatment (%)

18. Leuven II- Intensive Insulin in MICU Patients with expected LOS >3 days Van den Berghe G et al. N Engl J Med. 2006;354;5:449-61 . * p<.05 * * *

19. Intensive Insulin Meta-analysis of 29 Trials 8432 Patients JAMA 2008;300(8):933-44

20. NICE-SUGAR Randomized trial of 6104 patients 42 hospitals in Australia, New Zealand, and Canada Enrolled patients with an expected LOS of 3 days and had an arterial line Intervention discontinued when patient was eating or discharged from ICU Reason for ICU admission: 37% Operative 63% Non-Operative Patients were randomized to: intensive treatment - infusion to maintain glucose between 81-108 mg/dl conventional treatment- targeting a glucose of <180mg/dl Mean glucose in the intensive treatment group was 115mg/dl and conventional group was 144mg/dl NEJM 2009;360:1283-97

21. NICE-SUGAR Results Critical Care Med 2008;36:12 1-8

22. How do we use this data to care for our patients?

23. American Diabetes Association 2009* “Standards of Medical Care” Diabetes Care 2009 32;Supp 1:S14-61 Circulation 2008;117;1610-19 Critical Care Med 2008 35:296-327 International Guidelines for Management of Severe Sepsis and Septic Shock: 2008 American Heart Association: Hyperglycemia and Acute Coronary Syndrome The Endocrine Society- Position Statement March 2009 * ADA/AACE statement March 09 promised new guidelines and recommended targets similar to the “conventional” arm of NICE-SUGAR <150 mg/dL 2C Critical E (Expert Consensus) <180-200mg/dL <126 mg/dL Noncritical <140 110 mg/dL Non-Fasting C A Evidence level <140 Critical non-surgical 110 mg/dL Critical surgical Fasting Patients <180 mg/dL 90-140 mg/dL C C Noncritical Critical <144-180 mg/dL Critical

24. Barriers to Inpatient Glucose Control Infection, fever, stress, glucocorticoids, surgery all exacerbate hyperglycemia Patients may eat less or have meals held Timing of insulin administration and meals are often disrupted Oral medications are often held

25. Limitations of Oral Agents for Managing In-Hospital Hyperglycemia Sulfonylureas No rapid dose adjustment Risk of hypoglycemia in patients not eating normally Metformin No rapid dose adjustment Mostly contraindicated due to increased risk of lactic acidosis in hospitalized patients (ie, intravenous contrast, renal failure, congestive heart failure) Thiazolidinediones No rapid dose adjustment Mostly contraindicated in heart failure, hepatic dysfunction Clement S et al. Diabetes Care . 2004;27:553-591.

27. Using Insulin in the Hospital First, Determine Source/Route of Nutrition Second, Estimate a Starting Dose of Scheduled Insulin Third, Know the Kinetics of the insulin you are using and make a plan

28. Source of Nutrition- Effects on Insulin Secretion Prandial insulin B L D B L D Basal insulin Basal insulin Basal insulin Prandial insulin The Eating Patient Pt. Receiving Continuous Feeds

29. Estimating a Starting Dose Use patient’s home regimen Adjust as clinically indicated Make a weight based estimate* Start 0.4units/kg for glucose 140-200 Start 0.5 units/kg for glucose 201-400 Consider lower starting dose with significant renal or hepatic impairment Estimate basal insulin and carb count Difficult to achieve in the hospital If attempting, estimate basal insulin (.2-.25 units/kg/day) Type I: Give 1 unit per 15g carbohydrates Type II: Give 1 unit per 10g carbohydrates Diabetes Care 30:2181-2186, 2007

30. Kinetics of Insulins Regular NPH 0 12 6 18 24 aspart/glulisine/lispro glargine

31. Mimicking Nature With Insulin Basal/Bolus Concept Physiologic Insulin Secretion Insulin (µU/mL) Glucose (mg/dL) 9 B L D 150 100 50 0 7 8 9 10 11 12 1 2 3 4 5 6 7 8 AM PM Time of Day Basal glucose Adapted from Bergenstal RM et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821 50 25 0 24-hr profile Basal insulin

32. Basal-Bolus Insulin Therapy: Insulin Glargine at HS and Mealtime Lispro or Aspart Insulin aspart/glulisine/lispro Insulin glargine B D L HS Insulin Effect Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy . New York, NY: Marcel Dekker Inc.; 2002:87

33. Example: Patient’s Total Daily Insulin Estimate=60 Units 10 units aspart glulisine lispro 10 units aspart glulisine lispro 10 units aspart glulisine lispro 30 units glargine Insulin Effect Adapted from Leahy J. In: Leahy J, Cefalu W, eds. Insulin Therapy . New York, NY: Marcel Dekker Inc.; 2002:87

34. Twice-Daily Split-Mixed Regimens Regular NPH B D L HS B Endogenous insulin Dawn phenomenon Hyperglycemia

35. Example: Patient’s Total Daily Insulin Estimate=60 Units 13 units NPH 27 units NPH 40 units of insulin in the a.m. 20 units of insulin in the p.m. +13 units regular +7 units regular

37. Insulin Requirement During Continuous Dextrose, TPN or Enteral Feedings, or Negligible Carbohydrate Exposure 8 12 6 10

38. Regimens for patient while NPO, on IV’s, or receiving continuous enteral feedings.

40. The Insulin Infusion

41. Many Protocols Exist DIGAMI (IV insulin glucose infusion followed by outpatient multidose subcutaneous insulin regimen) van den Berghe (IV insulin therapy to maintain blood glucose between 80 and 110 mg/dL) Portland protocol (perioperative use of IV insulin) Markovitz (IV insulin therapy to maintain blood glucose between 120 and 199 mg/dL) Yale Protocol (IV insulin therapy to maintain blood glucose between 100 and 139 mg/dL) Stamford Protocol (IV/SQ insulin only given if glucose is greater than 140) Duke Protocol (IV insulin to maintain blood glucose 101-150) Malmberg K. BMJ. 1997;314(7093):1512–1515. van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367. Markovitz LJ, et al. Endocr Pract . 2002;8:10–18. Goldberg PA, et al. Diabetes Care . 2004;27:461–467. Krinsley JS. Mayo Clin Proc . 2004;79:992-1000. Lien LF., et al. Endocr Pract . 2005;11: 240-53.

43. Peri-Procedural Management 8 12 6 10 Regular NPH Hold short acting insulin and give ½ regular dose of NPH

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